C1QTNF4

Summary

C1QTNF4 (C1q and TNF related 4, HGNC:14346) is a protein-coding gene on chromosome 11p11.2, encoding Complement C1q tumor necrosis factor-related protein 4 (Q9BXJ3). May be involved in the regulation of the inflammatory network. It is a selective cancer dependency (DepMap: 22.8% of cell lines).

Predicted to enable cytokine activity. Involved in positive regulation of cytokine production and positive regulation of signal transduction. Located in extracellular space.

Source: NCBI Gene 114900 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 82 total
• Cancer dependency (DepMap): dependent in 22.8% of screened cell lines
• MANE Select transcript: NM_031909

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14346
Approved symbol	C1QTNF4
Name	C1q and TNF related 4
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	CTRP4, ZACRP4
Ensembl gene	ENSG00000172247
Ensembl biotype	protein_coding
OMIM	614911
Entrez	114900

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000302514, ENST00000530097, ENST00000862513, ENST00000954826

RefSeq mRNA: 1 — MANE Select: NM_031909 NM_031909

CCDS: CCDS7942

Canonical transcript exons

ENST00000302514 — 2 exons

Exon	Start	End
ENSE00001143278	47589667	47590815
ENSE00001379832	47594148	47594411

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 96.29.

FANTOM5 (CAGE): breadth broad, TPM avg 8.6736 / max 806.3690, expressed in 330 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119649	5.3579	300
119648	2.5026	274
119647	0.4631	137
119650	0.1467	77
119651	0.1075	59
119646	0.0958	35

Top tissues by expression

138 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primary visual cortex	UBERON:0002436	96.29	gold quality
superior frontal gyrus	UBERON:0002661	96.09	gold quality
nucleus accumbens	UBERON:0001882	95.47	gold quality
putamen	UBERON:0001874	95.13	gold quality
caudate nucleus	UBERON:0001873	94.23	gold quality
cortical plate	UBERON:0005343	93.04	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.53	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.88	gold quality
right frontal lobe	UBERON:0002810	91.30	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.31	gold quality
anterior cingulate cortex	UBERON:0009835	89.85	gold quality
temporal lobe	UBERON:0001871	89.21	gold quality
amygdala	UBERON:0001876	89.04	gold quality
cerebellum	UBERON:0002037	88.52	gold quality
cerebellar cortex	UBERON:0002129	88.35	gold quality
cerebellar hemisphere	UBERON:0002245	88.16	gold quality
Ammon’s horn	UBERON:0001954	87.40	gold quality
brain	UBERON:0000955	87.24	gold quality
hypothalamus	UBERON:0001898	86.14	gold quality
substantia nigra	UBERON:0002038	84.64	gold quality
cerebral cortex	UBERON:0000956	84.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.49	gold quality
pituitary gland	UBERON:0000007	82.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.54	silver quality
embryo	UBERON:0000922	82.01	gold quality
ganglionic eminence	UBERON:0004023	82.01	gold quality
adenohypophysis	UBERON:0002196	79.39	gold quality
left ovary	UBERON:0002119	78.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	77.46	gold quality
right ovary	UBERON:0002118	76.78	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	129.99
E-ANND-3	no	2.20

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 22.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• CTRP4 is a novel tumor-promoting inflammatory regulator. (PMID:21658842)
• These results establish CTRP4 as a novel nutrient-responsive central regulator of food intake and energy balance. (PMID:24366864)
• In a Pakistani family with retinal degeneration, whole-exome sequencing identified 2 homozygous missense variants: c.1304G>A; p.Arg435Gln in ZNF408 (NM_024741) and c.902G>A; p.Gly301Asp in C1QTNF4 (NM_031909). Both segregated with the retinal phenotype in this family and were absent in ethnically matched control chromosomes. (PMID:29721947)
• C1QTNF4 gene p.His198Gln mutation is correlated with early-onset systemic lupus erythematosus in Iranian patients. (PMID:33009720)
• Increased serum C1q/TNF-related protein 4 concentration in patients with acute coronary syndrome. (PMID:34801485)
• C1q tumor necrosis factor-related protein 4 is associated with coronary artery disease in patients with type 2 diabetes. (PMID:35598316)
• Serum C1q/TNF-Related Protein 4 Levels are Associated with Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Patients. (PMID:36787473)
• CTRP4 ameliorates inflammation, thereby attenuating the interaction between HUVECs and THP-1 monocytes through SIRT6/Nrf2 signaling. (PMID:38016337)
• Association of serum CTRP4 levels with vascular endothelial function in patients with type 2 diabetes mellitus: CTRP4 ameliorating inflammation, proliferation and migration in human umbilical vein endothelial cells. (PMID:38286878)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	c1qtnf4	ENSDARG00000024299
mus_musculus	C1qtnf4	ENSMUSG00000040794
rattus_norvegicus	C1qtnf4	ENSRNOG00000081381

Paralogs (23): C1QTNF3 (ENSG00000082196), COL19A1 (ENSG00000082293), PDCD7 (ENSG00000090470), COL10A1 (ENSG00000123500), C1QL1 (ENSG00000131094), C1QTNF6 (ENSG00000133466), C1QL2 (ENSG00000144119), COL8A1 (ENSG00000144810), C1QTNF2 (ENSG00000145861), C1QC (ENSG00000159189), C1QTNF7 (ENSG00000163145), C1QL3 (ENSG00000165985), COL8A2 (ENSG00000171812), C1QB (ENSG00000173369), C1QA (ENSG00000173372), C1QTNF1 (ENSG00000173918), ADIPOQ (ENSG00000181092), OTOL1 (ENSG00000182447), C1QTNF8 (ENSG00000184471), C1QL4 (ENSG00000186897), C1QTNF9B (ENSG00000205863), C1QTNF5 (ENSG00000223953), C1QTNF9 (ENSG00000240654)

Protein

Protein identifiers

Complement C1q tumor necrosis factor-related protein 4 — Q9BXJ3 (reviewed: Q9BXJ3)

Alternative names: C1q/TNF-related protein 4

All UniProt accessions (3): A0A3B0J0L9, E9PPZ5, Q9BXJ3

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in the regulation of the inflammatory network. Its role as pro- or anti-inflammatory seems to be context dependent. Seems to have some role in regulating food intake and energy balance when administered in the brain. This effect is sustained over a two-day period, and it is accompanied by decreased expression of orexigenic neuropeptides in the hypothalamus 3 hours post-injection.

Subunit / interactions. Homomultimer. Forms trimers, hexamers and high molecular weight oligomers.

Subcellular location. Secreted.

Tissue specificity. Widely expressed at low levels. Highest levels in adipocyte tissue and brain.

Induction. Up-regulated by IL6.

RefSeq proteins (1): NP_114115* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001073	C1q_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR050822	Cerebellin_Synaptic_Org	Family

Pfam: PF00386

UniProt features (8 total): domain 2, sequence variant 2, signal peptide 1, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXJ3-F1	86.63	0.70

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 124 (showing top): GOBP_BEHAVIOR, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_RESPONSE_TO_DIETARY_EXCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_PROTEIN_IMPORT, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, TAL1ALPHAE47_01, GOBP_POSITIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_SUPERFAMILY_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_EATING_BEHAVIOR, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_POSITIVE_REGULATION_OF_NON_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_MYELOID_LEUKOCYTE_ACTIVATION

GO Biological Process (7): reduction of food intake in response to dietary excess (GO:0002023), gene expression (GO:0010467), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of interleukin-6-mediated signaling pathway (GO:0070105), cell surface receptor signaling pathway via STAT (GO:0097696), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224)

GO Molecular Function (2): cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to dietary excess	1
eating behavior	1
macromolecule biosynthetic process	1
positive regulation of cytokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
positive regulation of cytokine-mediated signaling pathway	1
interleukin-6-mediated signaling pathway	1
regulation of interleukin-6-mediated signaling pathway	1
cell surface receptor signaling pathway	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C1QTNF4	FAM180B	Q6P0A1	550
C1QTNF4	ANKRD24	Q8TF21	493
C1QTNF4	MTCH2	Q9Y6C9	488
C1QTNF4	C1QTNF12	Q5T7M4	397
C1QTNF4	C17orf58	Q2M2W7	388
C1QTNF4	PLEKHM1	Q9Y4G2	381
C1QTNF4	CTXND1	A0A1B0GTU2	371
C1QTNF4	STK32A	Q8WU08	368
C1QTNF4	TMEM121	Q9BTD3	341
C1QTNF4	PLEKHG1	Q9ULL1	340
C1QTNF4	SLC39A13	Q96H72	329
C1QTNF4	ZCWPW1	Q9H0M4	323
C1QTNF4	MAMDC4	Q6UXC1	312
C1QTNF4	NPIPB9	F8W1W9	310
C1QTNF4	ITPRID1	Q6ZRS4	307

IntAct

15 interactions, top by confidence:

A	B	Type	Score
C1QTNF4	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
L3MBTL3	C1QTNF4	psi-mi:“MI:0915”(physical association)	0.560
C1QTNF4	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
C1QTNF4	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
TEPSIN	C1QTNF4	psi-mi:“MI:0915”(physical association)	0.560
ADIPOQ	C1QL1	psi-mi:“MI:0914”(association)	0.530
NP	TRIM66	psi-mi:“MI:0914”(association)	0.350
C1QTNF4	L3MBTL3	psi-mi:“MI:0915”(physical association)	0.000
C1QTNF4	UBQLN1	psi-mi:“MI:0915”(physical association)	0.000
C1QTNF4	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): C1QTNF4 (Two-hybrid), C1QTNF4 (Two-hybrid), UBQLN2 (Two-hybrid), L3MBTL3 (Two-hybrid), C1QTNF4 (Affinity Capture-MS)

ESM2 similar proteins: A2BDX3, A8MY62, B0F2B4, D3KU66, D3KU67, D3Z7H8, O00634, O19179, O43323, O62763, O88941, O94766, P08294, P15289, P15589, P18080, P21836, P22303, P23795, P35475, P36196, P41975, P50427, P50428, P51688, P51689, P52785, P55203, Q01634, Q02846, Q08DD1, Q10PI6, Q14DK5, Q29499, Q495W5, Q5ZMM1, Q61488, Q68FV3, Q69ZQ1, Q6NSJ0

Diamond homologs: A0A060WQA3, A5PN28, A6NHN0, B2RNN3, O75973, O88992, P02745, P02746, P08125, P0C862, P14106, P14282, P23206, P25067, P25318, P27658, P31720, P31721, P83371, P98085, Q00780, Q02105, Q03692, Q05306, Q05A80, Q06576, Q0II24, Q15848, Q2KIU3, Q2KIX7, Q3Y5Z3, Q4ZJM7, Q4ZJN1, Q5E9E3, Q5FVH0, Q5RJ80, Q5VWW1, Q60994, Q69DL0, Q6IMN6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

82 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

163 predictions. Top by Δscore:

Variant	Effect	Δscore
11:47594143:CTCA:C	donor_loss	0.9900
11:47594144:TCACC:T	donor_loss	0.9900
11:47594145:CA:C	donor_loss	0.9900
11:47594147:CCTGG:C	donor_gain	0.9900
11:47592558:A:C	donor_gain	0.9700
11:47590813:CGC:C	acceptor_gain	0.9600
11:47590813:CGCCT:C	acceptor_loss	0.9500
11:47590815:CCTGG:C	acceptor_loss	0.9500
11:47590816:C:A	acceptor_loss	0.9500
11:47590816:C:CC	acceptor_gain	0.9500
11:47590817:T:A	acceptor_loss	0.9500
11:47594146:A:AC	donor_gain	0.9400
11:47594147:C:CC	donor_gain	0.9400
11:47594517:T:TA	donor_gain	0.9400
11:47594532:T:TA	donor_gain	0.9400
11:47590828:C:CT	acceptor_gain	0.9200
11:47590829:G:T	acceptor_gain	0.9200
11:47592527:ACC:A	donor_gain	0.9100
11:47592528:CCC:C	donor_gain	0.9100
11:47590811:GGCGC:G	acceptor_gain	0.8800
11:47592523:TCC:T	donor_gain	0.8800
11:47593604:C:A	donor_gain	0.8700
11:47590812:GCGC:G	acceptor_gain	0.8600
11:47590813:CGCC:C	acceptor_gain	0.8600
11:47593590:C:A	donor_gain	0.8500
11:47592529:CCC:C	donor_gain	0.8400
11:47592642:CCTGA:C	acceptor_gain	0.8300
11:47593213:T:TA	donor_gain	0.8200
11:47594523:T:C	donor_gain	0.8200
11:47590814:GC:G	acceptor_gain	0.8100

AlphaMissense

2100 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:47589888:C:T	G308D	0.999
11:47589917:G:C	S298R	0.999
11:47589917:G:T	S298R	0.999
11:47589918:C:A	S298I	0.999
11:47589919:T:G	S298R	0.999
11:47589960:A:T	V284D	0.999
11:47590071:A:G	L247P	0.999
11:47590119:A:G	F231S	0.999
11:47590126:A:C	Y229D	0.999
11:47590142:G:C	C223W	0.999
11:47590149:A:G	F221S	0.999
11:47590353:C:T	G153D	0.999
11:47590578:A:G	F78S	0.999
11:47590585:A:C	Y76D	0.999
11:47590608:A:G	F68S	0.999
11:47590715:G:C	F32L	0.999
11:47590715:G:T	F32L	0.999
11:47590717:A:G	F32L	0.999
11:47589889:C:G	G308R	0.998
11:47589894:A:G	F306S	0.998
11:47590143:C:T	C223Y	0.998
11:47590149:A:C	F221C	0.998
11:47590170:A:G	F214S	0.998
11:47590274:G:C	F179L	0.998
11:47590274:G:T	F179L	0.998
11:47590275:A:G	F179S	0.998
11:47590276:A:G	F179L	0.998
11:47590359:A:G	F151S	0.998
11:47590434:A:T	L126H	0.998
11:47590530:A:G	L94P	0.998

dbSNP variants (sampled 300 via entrez): RS1000508382 (11:47596730 C>T), RS1000518136 (11:47591342 G>A,T), RS1000560398 (11:47596445 A>T), RS1001120002 (11:47589324 C>T), RS1001178393 (11:47596963 A>G), RS1001368415 (11:47591718 A>G), RS1001467928 (11:47589588 G>A,C,T), RS1001777910 (11:47593030 C>A,G,T), RS1002926956 (11:47589445 G>A), RS1003190225 (11:47594353 G>A), RS1003390607 (11:47594795 G>A), RS1003494206 (11:47589659 C>A,T), RS1004147742 (11:47595634 T>C,G), RS1004365730 (11:47590951 C>G,T), RS1004501349 (11:47595909 A>G,T)

Disease associations

OMIM: gene MIM:614911 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST005232_56	Neuroticism	1.000000e-16
GCST006923_11	Loneliness	1.000000e-07
GCST006924_13	Loneliness (MTAG)	1.000000e-08
GCST007293_118	Body fat distribution (arm fat ratio)	3.000000e-08
GCST007293_19	Body fat distribution (arm fat ratio)	2.000000e-10
GCST007293_45	Body fat distribution (arm fat ratio)	5.000000e-14
GCST007294_28	Body fat distribution (trunk fat ratio)	6.000000e-09
GCST007294_9	Body fat distribution (trunk fat ratio)	4.000000e-06
GCST007295_159	Body fat distribution (leg fat ratio)	1.000000e-18
GCST007295_24	Body fat distribution (leg fat ratio)	7.000000e-08
GCST007295_50	Body fat distribution (leg fat ratio)	2.000000e-12
GCST007323_91	Risk-taking tendency (4-domain principal component model)	1.000000e-09
GCST007559_27	Sleep duration (short sleep)	4.000000e-08
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16
GCST008103_60	Bipolar disorder	5.000000e-07
GCST010002_238	Refractive error	2.000000e-14
GCST010136_2	Fruit consumption	5.000000e-09
GCST010703_36	Brain morphology (MOSTest)	8.000000e-09
GCST90002405_280	Reticulocyte count	9.000000e-12
GCST90002406_368	Reticulocyte fraction of red cells	2.000000e-14

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0007865	loneliness measurement
EFO:0004341	body fat distribution
EFO:0008579	risk-taking behaviour
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	6
trichostatin A	affects cotreatment, decreases expression	3
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
GSK-J4	increases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Gold Compounds	increases expression	1
Antirheumatic Agents	increases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases expression, increases abundance	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.